Lidocaine and similar compounds have been used for the treatment of cardiac arrhythmias, however, while the same are used in coronary intensive care units, it cannot be used in the prophylaxis of the sudden death syndrome because its biological half life is only about 75 minutes. Furthermore, the absorption of lidocaine from the intestinal tract is unsatisfactory and this substance provides undesirable side effects such as hypotension, neurotoxicity and low therapeutic index. Still further, due to the rapid metabolism thereof, the lidocaine must be administered by continuous intravenous infusion in order to maintain adequate plasma concentrations.
Consequently, there has been continuous research in the field to try to provide agents with improved antiarrhythmic action.
French Pat. No. 1,566,045 to Aktiebolaget Astra describes the general group of compounds of the formula: ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen, halogen or loweralkyl. The patent also describes the production of these compounds by converting the quinuclidine carboxylic acid to its methyl ester followed by treatment with a mixture of methylmagnesium iodide and the selected aniline. However, yields are low and are contaminated with undesired side products.
The French patent specifically discloses the 2,6,-xylidide of quinuclidine-2-carboxylic acid and the compound is indicated as having antiarrhythmic and local anaesthetic action. However, our tests have proved that this compound is neurotoxic and is completely devoid of any useful antiarrhythmic action.
The article of Dahlbom and Dolby in Acta Pharma. Suecica 65. 277 (1969) describes various derivatives of quinuclidine-3-carboxylic acid including the compound N-(quinuclidine-3-carbonyl)-2,6-dimethylaniline, which compounds were tested for various pharmacological and microbiological activities and were found to have no pharmacological effect except for a weak local anaesthetic action.
The compounds are produced according to the article in Acta Pharm. Suecica by reacticing the quinuclidine carboxylic acid hydrochloride with the aniline e.g. 2,6-dimethylaniline under refluxing in the presence of thionyl chloride. However, this reaction causes extensive discoloration of the reaction mixture and in the formation of sulfur-containing material of unknown composition which contaminates the desired product. The yield of partially purified product by this procedure can rarely exceed 60% of the theoretical.